Oral Delivery of Particulate Transforming Growth Factor Beta 1 and All-Trans Retinoic Acid Reduces Gut Inflammation in Murine Models of Inflammatory Bowel Disease.

Abstract

BACKGROUND AND AIMS:

We investigated oral delivery of transforming growth factor beta 1 [TGFβ]- and all-trans retinoic acid [ATRA]-loaded microspheres as therapy for gut inflammation in murine models of inflammatory bowel disease [IBD].

METHODS:

ATRA and TGFβ were separately encapsulated in poly [lactic-co-glycolic] acid or polylactic acid microspheres [respectively]. TGFβ was encapsulated using proprietary phase-inversion nanoencapsulation [PIN] technology.

RESULTS:

PIN particles provided sustained release of bioactive protein for at least 4 days and were stable for up to 52 weeks when stored at either 4(0)C or -20(0)C. In the SCID mouse CD4 + CD25- T cell transfer model of IBD, oral treatment starting at disease onset prevented weight loss, significantly reduced average disease score [~ 50%], serum amyloid A levels [~ 5-fold], colon weight-to-length ratio [~ 50%], and histological score [~ 5-fold].

CONCLUSIONS:

Both agents given together outperformed either separately. Highest TGFβ doses and most frequent dose schedule were most effective. Activity was associated with a significant increase [45%] in Foxp3 expression by colonic lamina propria CD4+ CD25+ T-cells. Activity was also demonstrated in dextran sulphate sodium-induced colitis. The data support development of the combination product as a novel, targeted immune based therapy for treatment for IBD.

• Authors: Thomas F Conway, Laura Hammer, Stacia Furtado, Edith Mathiowitz, Ferdinando Nicoletti, Katia Mangano, Nejat K Egilmez, Dominick L Auci
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 9 Issue 8 Pg. 647-58 (Aug 2015) ISSN: 1876-4479 [Electronic] England
• PMID: 25987350 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Anti-Inflammatory Agents
• Biomarkers
• Transforming Growth Factor beta
• Tretinoin

Topics

• Administration, Oral
• Animals
• Anti-Inflammatory Agents (administration & dosage, therapeutic use)
• Biomarkers (metabolism)
• Drug Administration Schedule
• Drug Therapy, Combination
• Female
• Inflammatory Bowel Diseases (drug therapy, metabolism, pathology)
• Intestinal Mucosa (metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Microspheres
• Transforming Growth Factor beta (administration & dosage, therapeutic use)
• Treatment Outcome
• Tretinoin (administration & dosage, therapeutic use)